Intracellular delivery of nuclear localization sequence peptide mitigates COVID-19 by inhibiting nuclear transport of inflammation-associated transcription factors.

The novel severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), responsible for coronavirus disease 2019 (COVID-19), can trigger dysregulated immune responses known as the cytokine release syndrome (CRS), leading to severe organ dysfunction and respiratory distress. Our study focuses on developing an improved cell-permeable nuclear import inhibitor (iCP-NI), capable of blocking the nuclear transport of inflammation-associated transcription factors, specifically nuclear factor kappa B (NF-κB). By fusing advanced macromolecule transduction domains and nuclear localization sequences from human NF-κB, iCP-NI selectively interacts with importin α5, effectively reducing the expression of proinflammatory cytokines. In mouse models mimic SARS-CoV-2-induced pneumonitis, iCP-NI treatment demonstrated a significant decrease in mortality rates by suppressing proinflammatory cytokine production and immune cell infiltration in the lungs. Similarly, in hamsters infected with SARS-CoV-2, iCP-NI effectively protected the lung from inflammatory damage by reducing tumor necrosis factor-α, interleukin-6 (IL-6), and IL-17 levels. These promising results highlight the potential of iCP-NI as a therapeutic approach for COVID-19-related lung complications and other inflammatory lung diseases.

Effects of myeloid immune cells on the metabolic process of biomimetic bone regeneration.

AIMS: As the process of bone regeneration is preceded by an inflammatory response, the immune system has long been considered important for fracture healing. Despite many studies on the contribution of immune cells to bone-related diseases, the role of immune cells in the regeneration therapy of lost bone is not well understood. In addition, various types of cells are involved in the clinical bone regeneration environment, but most of the osteo-biology studies are conducted in an osteoblast-only environment. MATERIALS AND METHODS: Here, we investigated the effects of macrophages and dendritic cells on osteogenic differentiation in a co-culture environment involving human periosteal cell-derived osteoblasts, human monocyte-derived osteoclasts, and myeloid-derived cells. In addition, the cluster of myeloid immune cells involved in the clinical bone regeneration process was analyzed through bone defect rat modeling. KEY FINDINGS: We found that specific types of myeloid cells and related cytokines increased osteogenic differentiation. These results were confirmed in experiments using myeloid cells originating from human primitive peripheral blood mononuclear cells and by measuring the colonization of macrophages and dendritic cells in an in vivo bone defect environment. In addition, Next generation sequencing (NGS) analysis was performed through RNA sequencing for osteogenesis caused by macrophages and dendritic cells in vitro, which implemented a clinical bone regeneration environment. The results of these experiments suggest that the role of M2 macrophages or dendritic cells is markedly increased during osteogenic differentiation. Therefore, we propose that the exchange of bioactive factors between macrophages and dendritic cells during the bone formation metabolic process is a crucial step of tissue regeneration rather than limited to the initial inflammatory response. SIGNIFICANCE: This study indicates that M2 macrophages, among myeloid cells, can be mediators that play a vital role in the effective bone regeneration process and shows the potential as a useful next-generation advanced cell therapy for bone regeneration treatment.

Implant Removal After Medial Opening Wedge High Tibial Osteotomy Provides Implant-Related Pain Relief and Functional Improvement.

PURPOSE: To (1) investigate the incidence of implant-related pain after medial opening wedge high tibial osteotomy (MOWHTO) using a locking plate, (2) determine whether implant removal provides pain relief and functional improvement, and (3) evaluate bone healing and loss of correction after implant removal. METHODS: Between March 2014 and September 2017, MOWHTO was performed without bone graft. The inclusion criteria were patients who underwent implant removal after MOWHTO and were followed up for a minimum of 2 years. Patients were evaluated for implant removal 1 and 2 years after surgery. Clinical and functional evaluations were conducted to investigate implant-related pain using the visual analog scale, Lysholm score, and Tegner score. The radiographic indices measured were the gap-filling rate, weightbearing line (WBL) ratio, hip-knee-ankle angle (HKAA), medial proximal tibial angle (MPTA), and posterior tibial slope angle (PTSA). RESULTS: A total of 55 patients were enrolled. Fifty-one (92.7%) patients experienced implant-related pain prior to implant removal, with 43 and 8 patients reporting mild pain and moderate pain, respectively. At 1 and 2 years after implant removal, mild pain occurred in 6 (10.9%) and 5 (9.1%) patients, respectively. The remaining patients reported no implant-related pain. Prior to implant removal and 1 year after implant removal, the Lysholm score improved from 77.0 ± 5.6 to 86.8 ± 5.7 (P < .001), and the Tegner score improved from 3.3 ± 1.2 to 3.9 ± 1.3 (P < .001). The mean gap-filling rate was 84.4% ± 9.6% at implant removal, and it significantly increased to 93.7% ± 5.4% and 97.4% ± 2.6% at 1 and 2 years after implant removal, respectively (P < .001). For the WBL ratio, HKAA, MPTA, and PTSA, no statistically significant differences were found after implant removal. CONCLUSIONS: The incidence of implant-related pain after MOWHTO using the medial proximal tibial locking plate was high. Implant removal provides pain relief and functional improvement (met minimal clinically important differences). Even after implant removal, bone healing progressed gradually without a loss of correction in all patients. LEVEL OF EVIDENCE: Level IV, case series.

Apigenin's Therapeutic Potential Against Viral Infection.

Several antiviral drugs are clinically approved to treat influenza that is a highly prevalent acute respiratory disease. However, emerging drug-resistant virus strains undermine treatment efficacy, highlighting the exigency for novel antiviral drugs to counter these drug-resistant strains. Plants and their derivates have been historically utilized as medicinal remedies, and extensive studies have evidenced the antiviral potential of phytochemicals. Notably, apigenin is a predominant flavonoid with minimal toxicity and substantial therapeutic effects in various disease models. Despite its many anti-inflammatory, anti-oxidant, anti-cancer, anti-bacterial, and other beneficial bioactivities, existing reviews have yet to focus on apigenin's antiviral effects. Therefore, this review elucidates apigenin's therapeutic and antiviral properties in vitro and in vivo, discussing its mode of action and future prospects. Apigenin's remarkable inhibition by modulating multiple mechanisms against viruses has promising potential for novel plant-derived antiviral drugs and further clinical study developments.

BMP-9 Improves the Osteogenic Differentiation Ability over BMP-2 through p53 Signaling In Vitro in Human Periosteum-Derived Cells.

Bone morphogenetic proteins (BMPs) have tremendous therapeutic potential regarding the treatment of bone and musculoskeletal disorders due to their osteo-inductive ability. More than twenty BMPs have been identified in the human body with various functions, such as embryonic development, skeleton genesis, hematopoiesis, and neurogenesis. BMPs can induce the differentiation of MSCs into the osteoblast lineage and promote the proliferation of osteoblasts and chondrocytes. BMP signaling is also involved in tissue remodeling and regeneration processes to maintain homeostasis in adults. In particular, growth factors, such as BMP-2 and BMP-7, have already been approved and are being used as treatments, but it is unclear as to whether they are the most potent BMPs that induce bone formation. According to recent studies, BMP-9 is known to be the most potent inducer of the osteogenic differentiation of mesenchymal stem cells, both in vitro and in vivo. However, its exact role in the skeletal system is still unclear. In addition, research results suggest that the molecular mechanism of BMP-9-mediated bone formation is also different from the previously known BMP family, suggesting that research on signaling pathways related to BMP-9-mediated bone formation is actively being conducted. In this study, we performed a phosphorylation array to investigate the signaling mechanism of BMP-9 compared with BMP-2, another influential bone-forming growth factor, and we compared the downstream signaling system. We present a mechanism for the signal transduction of BMP-9, focusing on the previously known pathway and the p53 factor, which is relatively upregulated compared with BMP-2.

Changes of resistance indices after medication in benign prostatic hyperplasia: a prospective study.

Background: This study aimed to determine the relationship between resistive indices (RIs) and changes in prostate size after medical treatment in patients with benign prostatic hyperplasia (BPH). Methods: A total of 86 patients with BPH were included in the study, excluding 42 patients with a total prostate volume (TPV) of <30 cc or taking α1-adrenergic blockers and 5α-reductase inhibitors (5ARI) before study participation. Therefore, the data for 44 patients were analyzed. All patients were treated with α1-adrenergic blockers and 5ARIs. The variables examined were prostate-specific antigen, International Prostate Symptom Score, quality of life score, maximal urinary flow rate, residual urine volume, TPV, transition zone volume, and RIs of the urethral artery and left and right capsular arteries. These variables were assessed at baseline and after 3 and 6 months of treatment. Results: The mean TPV was 43.5 ± 10.9 and decreased to 35.2 ± 11.5 and 33.9 ± 9.8 after 3 and 6 months of treatment, respectively (p < 0.001). The mean RI of the urethral artery, right capsular artery, and left capsular artery at pretreatment did not decrease significantly. However, comparing the baseline with 3-month data, TPV at 3 months/TPV at baseline was significantly correlated with RI changes in the left capsular artery (r = 758; P < 0.001). Conclusion: In patients with BPH, α1-adrenergic blocker and 5ARI medications for 3 and 6 months did not result in a significant reduction in the RI of the urethral artery and both capsular arteries. Larger scale, prospective studies are needed to evaluate the relationship between TPV and RI reductions.

Downregulation of DNA methylation enhances differentiation of THP-1 cells and induces M1 polarization of differentiated macrophages.

DNA methylation is an epigenetic modification that regulates gene expression and plays an essential role in hematopoiesis. UHRF1 and DNMT1 are both crucial for regulating genome-wide maintenance of DNA methylation. Specifically, it is well known that hypermethylation is crucial characteristic of acute myeloid leukemia (AML). However, the mechanism underlying how DNA methylation regulates the differentiation of AML cells, including THP-1 is not fully elucidated. In this study, we report that UHRF1 or DNMT1 depletion enhances the phorbol-12-myristate-13-acetate (PMA)-induced differentiation of THP-1 cells. Transcriptome analysis and genome-wide methylation array results showed that depleting UHRF1 or DNMT1 induced changes that made THP-1 cells highly sensitive to PMA. Furthermore, knockdown of UHRF1 or DNMT1 impeded solid tumor formation in xenograft mouse model. These findings suggest that UHRF1 and DNMT1 play a pivotal role in regulating differentiation and proliferation of THP-1 cells and targeting these proteins may improve the efficiency of differentiation therapy in AML patients.

Plant-derived PAP proteins fused to immunoglobulin A and M Fc domains induce anti-prostate cancer immune response in mice.

In this study, recombinant Fc-fused Prostate acid phosphatase (PAP) proteins were produced in transgenic plants. PAP was fused to immunoglobulin (Ig) A and M Fc domain (PAP-IgA Fc and PAP-IgM Fc), which were tagged to the ER retention sequence KDEL to generate PAP-IgA FcK and PAP-IgM FcK. Agrobacteriummediated transformation was performed to produce transgenic tobacco plants expressing four recombinant proteins. Genomic PCR and RT-PCR analyses confirmed the transgene insertion and mRNA transcription of PAP-IgA Fc, PAP-IgM Fc, PAP-IgA FcK, and PAP-IgM FcK in tobacco plant leaves. Western blot confirmed the expression of PAP-IgA Fc, PAP-IgM Fc, PAP-IgA FcK, and PAP-IgM FcK proteins. SEC-HPLC and Bio-TEM analyses were performed to confirm the size and shape of the plant-derived recombinant PAP-Fc fusion proteins. In mice experiments, the plant-derived IgA and IgM Fc fused proteins induced production of total IgGs including IgG1 against PAP. This result suggests that IgA and IgM Fc fusion can be applied to produce recombinant PAP proteins as a prostate cancer vaccine in plant expression system. [BMB Reports 2023; 56(7): 392-397].

Current treatment patterns within 1 year after prostate cancer diagnosis in Korean patients over 75 years old: a retrospective multicenter study.

Background: We aimed to evaluate the current status of first-line treatment options for prostate cancer in patients aged ≥75 years in Korea. Materials and methods: The study included 873 patients diagnosed with biopsy-proven prostate cancer at 5 institutions in Korea from January 2009 to December 2018. Inclusion criteria were aged ≥75 years at diagnosis, prostate biopsy with ≥12 cores, and follow-up period ≥1 year. Clinical data were retrospectively collected from electronic medical records. Results: Primary treatment for prostate cancer in patients aged ≥75 years included androgen deprivation therapy (ADT) (n = 614), radical prostatectomy (RP) (n = 114), and radiation therapy (n = 62). Among patients with RP, nine patients received ADT before RP. The RP group was younger with better Eastern Cooperative Oncology Group Performance Status (ECOG PS), lower initial prostate-specific antigen (PSA), Gleason score (GS), max percent positive cores, less positive cores, and less advanced clinical Tumor Node Metastasis (TNM) stage compared with the ADT group. Multivariate analysis showed that age, ECOG PS, and PSA were independent prognostic factors for RP. When the ADT group was classified by therapeutic regimens, the most common therapeutic regimen was maximal androgen blockade (MAB) (n = 571), and leuprolide + bicalutamide (n = 330) was the most common MAB regimen. Multivariate analysis for secondary treatment showed that age, ECOG PS, GS, and clinical N1 or M1 stage were independent predictive factors. Enzalutamide was the most preferred treatment for tertiary treatment. Conclusion: In patients with prostate cancer aged ≥75 years, the most common treatment option was MAB, and the leuprolide + bicalutamide was the most common MAB regimen. Age, ECOG PS, and PSA are the useful indicators of surgical treatment, which increased during the study period. Younger patients with high GS and advanced clinical stage were more likely to undergo secondary treatment.

Galectin-4 increases the ability of M2 macrophages to enhance antiviral CD4+ T-cell responses.

Galectin-4 (Gal-4) is a ß-galactoside-binding protein belonging to the galectin family. Although Gal-4 is known to be involved in several physiologic processes of the gastrointestinal tract, its immunomodulatory roles remain unclear. In this study, we investigated whether Gal-4 influences the function of M1 and M2 macrophages. Gal-4 treatment drove more robust changes in the gene expression of M2 macrophages compared to M1 macrophages. Antiviral immune response-related genes were significantly upregulated in Gal-4-treated M2 macrophages. Gal-4 significantly enhanced the immunostimulatory activity of M2 macrophages upon Toll-like receptor 7 stimulation or infection with lymphocytic choriomeningitis virus (LCMV). Moreover, the antibody production against LCMV infection and the antiviral CD4+ T-cell responses, but not the antiviral CD8+ T-cell responses, were greatly increased by Gal-4-treated M2 macrophages in vivo. The present results indicate that Gal-4 enhances the ability of M2 macrophages to promote antiviral CD4+ T-cell responses. Thus, Gal-4 could be used to boost antiviral immune responses.

The orientation of the ALL femoral tunnel to minimize collision with the ACL tunnel depends on the need or not of far-cortex drilling.

PURPOSE: To (1) evaluate the optimal drill orientation of the anterolateral ligament (ALL) femoral tunnel to minimize collision with the anterior cruciate ligament (ACL) femoral tunnel during anatomical ACL reconstruction according to the need for far-cortex drilling and (2) investigate the geometric factors that affect tunnel collision secondary to drill orientation of the ALL femoral tunnel. METHODS: A three-dimensional femoral model of patients who underwent anatomical single-bundle ACL reconstruction between 2015 and 2016 was constructed, and the geometric factors were evaluated. Virtual ALL femoral tunnels were created to simulate 45 drilling conditions. For each condition, whether the virtual ALL femoral tunnel and its trajectory violated the femoral cortex and the minimum distance between tunnels was investigated. RESULTS: Thirty-nine subjects were included. Overall violation rates of the femoral cortex by the ALL tunnels and its trajectories were 11.1% (195 of 1755 conditions) and 40.7% (714 of 1755 conditions), respectively. A drilling angle of axial 0° and coronal - 40° showed the longest minimum distance between tunnels without femoral cortex violation by the ALL tunnel (6.3 ± 4.0 mm; collision rate 2.6% [1 of 39 subjects]). With simultaneous consideration of the ALL tunnel's trajectory representing far-cortex drilling, a drill angle of axial 40° and coronal 10° showed the longest minimum distance between tunnels without femoral cortex violation (0.6 ± 3.9 mm; collision rate 38.5% [15 of 39 subjects]). For surgical techniques requiring far-cortex drilling, regression analyses were performed on geometric factors that could affect tunnel collision, which revealed that the sagittal inclination angle of the ACL and the distance between the ACL femoral tunnel's outlet and ALL's femoral attachment were associated with tunnel collision. CONCLUSION: The optimal drill orientations of the ALL femoral tunnel to minimize collision with the ACL femoral tunnel were axial 0° and coronal - 40° for surgical techniques not requiring far-cortex drilling and axial 40° and coronal 10° for techniques requiring far-cortex drilling. For techniques requiring far-cortex drilling, additional adjustment for orientation of the ACL femoral tunnel is required to reduce the risk of tunnel collision. Therefore, an individualized surgical strategy should be applied according to the graft fixation method of the ALL femoral tunnel.

Bone healing on serial plain radiographs occurs slowly but adequately after medial opening wedge high tibial osteotomy without bone graft.

PURPOSE: The purpose of this study was to prospectively investigate osteotomy gap filling rates on serial plain radiographs, and to evaluate whether alignment correction is maintained after medial opening wedge high tibial osteotomy (MOWHTO) using a locking plate without bone graft. METHODS: Between March 2014 and June 2017, MOWHTO was performed without bone graft regardless of gap size. Radiographs were taken preoperatively, postoperatively, at 1, 3, 6, 12, 18, and 24 months after surgery. Radiographic examinations included a weight bearing long-standing anteroposterior (AP) view of the whole lower extremity, as well as, the AP, lateral, and both oblique views of the knee. Bone healing was measured on the medial oblique view of the knee. The postoperative alignment correction and its maintenance were assessed using the three radiologic parameters of the weight-bearing line (WBL) ratio, the hip-knee-ankle angle (HKAA), and the medial proximal tibial angle (MPTA) on the weight-bearing long-standing AP view of the lower extremity. RESULTS: Fifty-two consecutive patients underwent MOWHTO, but three patients failed to follow-up for more than 24 months. A total of 49 patients were assessed in this study. The median opening gap height was 10.0 mm (IQR, 8.0-12.0; range, 7-20). On immediate post-operative radiographs, the mean gap filling was 31.4 ± 3.6%. After 1, 3, 6, 12, 18, and 24 months, the mean gap filling rates increased to 38.7 ± 4.4%, 51.4 ± 6.6%, 66.5 ± 5.1%, 84.8 ± 7.0%, 92.4 ± 5.6%, and 97.8 ± 2.3%, respectively. Statistical differences were observed between all the follow-up evaluations (P < 0.001). Statistical differences in the WBL ratio, HKAA, and MPTA were observed between preoperatively and 1 month after surgery (P < 0.001). The mean PTSA increased significantly from preoperatively to postoperatively (P < 0.001). However, no statistical differences were found between the post-operative follow-up radiographs performed for these four values. CONCLUSION: MOWHTO using a locking plate without bone graft achieved at least 90% bone healing and had no loss in correction at 2 years postoperatively. LEVEL OF EVIDENCE: III.

Preclinical evaluation of Zanthoxylum piperitum Benn., traditional muscle pain remedy, for joint inflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Zanthoxylum piperitum has been used as a traditional Asian medicine to treat hypertension, stroke, bruise and muscle pain. It has been known to induce detoxification; affect anti-bacterial, anti-oxidant, and tyrosinase activity; inhibit osteosarcoma proliferation; anti-osteoarthritis inflammation. In this study, we aim to identify the therapeutic effect of Z. piperitum 90% EtOH extract (ZPE-LR) on rheumatoid arthritis. MATERIAL AND METHODS: We investigated the anti-rheumatoid arthritis and -immunomodulatory activities of the ZPE-LR in collagen-induced arthritic (CIA) mice, a rheumatoid arthritis animal model. In order to assess the analgesic effects of ZPE-LR in vivo, acetic acid injection, formaldehyde injection, hot plate model was used. The mechanism for anti-inflammatory activity of ZPE-LR was identified with LPS-stimulated Raw 264.7 cells. RESULTS: Pharmacologically, oral administration of ZPE-LR into CIA mice resulted in a significant and dose-dependent decrease in clinical arthritis score and paw swelling compared to untreated negative control. Pathologic examination showed that ZPE-LR prevented morphological change in cartilage and destruction of phalanges in CIA mice. This protective effect was associated with reduced pain, inflammatory mediators such as NO, TNF-α, IL-1ß, and IL-6, as well as COX-2 and iNOS expression. Furthermore, reduction of phosphor-ERK and BDNF indicates a novel rheumatoid arthritis-regulating mechanism by ZPE-LR treatment. CONCLUSIONS: These data suggest that the administration of ZPE-LR remarkably inhibited CIA progression and might be helpful in suppressing inflammation and pain in rheumatoid arthritis.

Optimal duration of preoperative antibiotic treatment prior to ureteroscopic lithotripsy to prevent postoperative systemic inflammatory response syndrome in patients presenting with urolithiasis-induced obstructive acute pyelonephritis.

PURPOSE: There is no consensus on the optimal duration of preoperative antibiotic treatment prior to ureteroscopic lithotripsy in patients presenting with urolithiasis-induced obstructive acute pyelonephritis (APN). We aimed to identify surgeon-modifiable, preoperative risk factors associated with postoperative systemic inflammatory response syndrome (SIRS) in these patients. MATERIALS AND METHODS: This multicenter retrospective study evaluated 115 patients who presented with urolithiasis-induced obstructive APN between January 2008 and December 2019. All patients were administered intravenous third-generation cephalosporin until culture sensitivity confirmation or until ureteroscopic lithotripsy. Data were collected for age, sex, diabetes mellitus, performance status, stone features, hydronephrosis grade, preoperative renal collecting system drainage, laboratory data, operative time, and duration of preoperative antibiotic treatment. Sensitivity analysis using Youden's index and logistic regression analysis were used to assess risk factors of postoperative SIRS. RESULTS: Postoperative SIRS was identified in 32 (27.8%) patients. The incidence of postoperative SIRS was higher in patients who received preoperative antibiotic treatment for fewer than 14 days (38.8% vs. 12.5%; p=0.001). Backward variable selection logistic regression analysis revealed maximal stone diameter ≥15 mm, duration of preoperative antibiotic treatment <14 days, and preoperative C-reactive protein (CRP) level ≥6.0 mg/L to be associated with higher risk of postoperative SIRS. CONCLUSIONS: Patients with urolithiasis-induced obstructive APN planned for ureteroscopic lithotripsy should be administered at least 14 days of preoperative antibiotic administration and achieve a serum CRP level ≤6.0 mg/L to minimize the risk of postoperative SIRS.

Biomechanical forces enhance directed migration and activation of bone marrow-derived dendritic cells.

Mechanical forces are pervasive in the inflammatory site where dendritic cells (DCs) are activated to migrate into draining lymph nodes. For example, fluid shear stress modulates the movement patterns of DCs, including directness and forward migration indices (FMIs), without chemokine effects. However, little is known about the effects of biomechanical forces on the activation of DCs. Accordingly, here we fabricated a microfluidics system to assess how biomechanical forces affect the migration and activity of DCs during inflammation. Based on the structure of edema, we proposed and experimentally analyzed a novel concept for a microchip model that mimicked such vascular architecture. The intensity of shear stress generated in our engineered chip was found as 0.2-0.6 dyne/cm2 by computational simulation; this value corresponded to inflammation in tissues. In this platform, the directness and FMIs of DCs were significantly increased, whereas the migration velocity of DCs was not altered by shear stress, indicating that mechanical stimuli influenced DC migration. Moreover, DCs with shear stress showed increased expression of the DC activation markers MHC class I and CD86 compared with DCs under static conditions. Taken together, these data suggest that the biomechanical forces are important to regulate the migration and activity of DCs.

Causes of necrotic features in fine-needle aspirates from cervical lymph nodes.

BACKGROUND: Lymph node fine-needle aspiration (LN FNA) cytology indicates necrosis in various diseases. Dominant necrotic features make the diagnosis of underlying conditions very difficult. METHODS: We retrospectively reviewed 460 patients who underwent cervical LN aspiration cytology that revealed necrotic findings at Keimyung University Dongsan Hospital in Daegu, Korea, from 2003-2017. Each specimen was evaluated and analyzed in association with the clinical findings, biopsy findings, and/or other ancillary tests, including acid-fast bacilli staining and molecular testing for Mycobacterium tuberculosis. RESULTS: When necrotic features were noted upon cervical LN FNA cytology, the most common pathologic LN FNA category was necrosis alone (31.5%). The second most common category was granulomatous inflammation (31.3%), followed by Kikuchi disease (20.0%) and malignant neoplasm (8.7%). In cases where the cervical LN FNA revealed necrosis alone, the most common final diagnosis was tuberculosis. In young patients, Kikuchi disease should be considered as one cervical LN FNA category, while metastatic carcinoma should be suspected in older patients. CONCLUSIONS: Even when necrosis alone is observed in LN FNA cytology, it is important to determine the cause through further evaluation.

Efficacy and safety of dose escalation in male patients with overactive bladder showing poor efficacy after low-dose antimuscarinic treatment: A retrospective multicenter study.

PURPOSE: To analyze the efficacy and safety of standard-dose antimuscarinic treatment on male patients with overactive bladder (OAB) symptoms showing poor efficacy after low-dose antimuscarinics. MATERIALS AND METHODS: We retrospectively reviewed the data of 566 male patients aged ≥40 with OAB symptoms between January 2017 and June 2018. They were treated with low-dose antimuscarinics for at least 4 weeks and showed poor efficacy; therefore, they were switched to standard dose antimuscarinic treatment (5 mg of solifenacin) for ≥12 weeks. The international prostate symptom score (IPSS) and overactive bladder symptom score (OABSS) at baseline (V0), 4 weeks (V1), and 12 weeks (V2) were analyzed. Post void residual urine volume (PVR) was also recorded. RESULTS: The median age, body mass index, and prostate-specific antigen levels were 69.0 years, 24.2 kg/m², and 1.24 ng/dL, respectively. The mean value of the total IPSS and OABSS significantly decreased between V0 and V2 (from 16.73 to 13.69 and 7.33 to 5.34, respectively, all p<0.001). All component scores from each questionnaire demonstrated a significant decrease except for numbers three and six on the IPSS questionnaire. PVR was increased from V0 to V2 (36.40 to 68.90 mL, p=0.015). Four and nine patients experienced constipation and thirst, respectively, and all adverse effects were graded as ≤2. CONCLUSIONS: Standard dose antimuscarinic treatment using solifenacin (5 mg) may be a safe and effective treatment for patients with OAB symptoms refractory to low-dose antimuscarinic treatment.

Initial conservative treatment of osteochondral fracture of the patella following first-time patellar dislocation.

BACKGROUND: There has been no gold standard of the initial treatment strategy for acute patellar dislocation (APD) with osteochondral fracture (OCF). Hence the study aim is firstly, to review and compare clinical outcomes of patients who underwent conservative treatment for APD with or without OCF. Secondly, to characterize the location and size of fracture fragment. METHODS: Sixty-nine consecutive patients who were retrospectively evaluated after first-time APD over a 2- year period were divided into two groups (group 1 (n = 24): APD with OCF and group 2 (n = 45): APD only). Magnetic resonance imaging (MRI) was used to assess patients with APD and OCF from the medial patella. All patients were treated with a supervised course of immobilization followed by progressive range of motion and strength exercise protocol. History of a recurrent dislocation, radiologic and functional scores were analyzed. RESULTS: Redislocation rate was 31.2% in group 1 and 26.6% in group 2, showing no significant difference between the two groups (p = 0.690). Intergroup differences in terms of final Kujala and IKDC scores were not significant (p = 0.117 and p = 0.283, respectively). Fracture sites of the patella in group 1 were classified as follows: patellar medial margin (12), inferomedial facet (7), and inferomedial facet involving central ridge (5). In the subgroup of patient with OCF of the inferomedial facet of the patella, the fragments were found in the lateral gutter and did not cause pain or mechanical symptoms. Thus, loose body removal was not performed. However, all five patients with large OCF involving the central ridge of the patella failed non-operative treatment with recurrent dislocations, ultimately requiring fragment refixation and medial retinacular imbrication. CONCLUSIONS: First, APD patients with OCFs of medial margin or inferomedial facet showed similar redislocation rates and functional knee scores with those without OCFs after conservative treatment. Second, initial conservative treatment failed in some APD patients with large OCF, especially when OCFs were fractured from inferomedial facet involving central ridge. Surgery should be considered with this type.

Maintenance of genome integrity and active homologous recombination in embryonic stem cells.

Embryonic stem cells (ESCs) possess specific gene expression patterns that confer the ability to proliferate indefinitely and enable pluripotency, which allows ESCs to differentiate into diverse cell types in response to developmental signals. Compared to differentiated cells, ESCs harbor an elevated level of homologous recombination (HR)-related proteins and exhibit exceptional cell cycle control, characterized by a high proliferation rate and a prolonged S phase. HR is involved in several aspects of chromosome maintenance. For instance, HR repairs impaired chromosomes and prevents the collapse of DNA replication forks during cell proliferation. Thus, HR is essential for the maintenance of genomic integrity and prevents cellular dysregulation and lethal events. In addition, abundant HR proteins in the prolonged S phase can efficiently protect ESCs from external damages and protect against genomic instability caused by DNA breaks, facilitating rapid and accurate DNA break repair following chromosome duplication. The maintenance of genome integrity is key to preserving the functions of ESCs and reducing the risks of cancer development, cell cycle arrest, and abnormal replication. Here, we review the fundamental links between the stem cell-specific HR process and DNA damage response as well as the different strategies employed by ESCs to maintain genomic integrity.

Biomechanical function of the anterolateral ligament of the knee: a systematic review.

BACKGROUND: It has been suggested that the anterolateral ligament (ALL) is an important anterolateral stabilizer of the knee joint which functions to prevent anterolateral subluxation and anterior subluxation at certain flexion angles in the knee. PURPOSE: To analyze and systematically interpret the biomechanical function of the ALL. METHODS: An online search was conducted for human cadaveric biomechanical studies that tested function of the ALL in resisting anterolateral subluxation and anterior subluxation of the knee. Two reviewers independently searched Medline, Embase, and the Cochrane Database of Systematic Reviews for studies up to 25 September 2018. Biomechanical studies not reporting the magnitude of anterior tibial translation or tibial internal rotation in relation to the function of the ALL were excluded. RESULTS: Twelve biomechanical studies using human cadavers evaluating parameters including anterior tibial translation and/or internal tibial rotation in anterior cruciate ligament (ACL)-sectioned and ALL-sectioned knees were included in the review. Five studies reported a minor increase or no significant increase in anterior tibial translation and internal tibial rotation with further sectioning of the ALL in ACL-deficient knees. Five studies reported a significant increase in knee laxity in tibial internal rotation or pivot shift with addition of sectioning the ALL in ACL-deficient knees. Two studies reported a significant increase in both anterior tibial translation and internal tibial rotation during application of the anterior-drawer and pivot-shift tests after ALL sectioning. CONCLUSION: There was inconsistency in the biomechanical characteristics of the ALL of the knee in resisting anterolateral and anterior subluxation of the tibia.